Process for preparing 3-hydroxy-2-methyl-4-pyrone

ABSTRACT

3-HYDROXY-2-METHYL-4-PYRONE (MALTOL) IS PREPARED BY (1) REACTING Beta , delta -DIOXOCAPROALDEHYDE DIALKYL ACETAL WITH LEAD TETRAACETATE, (2) EITHER (A) PYROLYZING THE PRODUCT OF STEP (1), OR (B) TREATING THE SAME WITH AN ACID CONDENSING AGENT, AND (3) HYDROLYZING THE PRODUCT OF STEP (2) EITHER SIMULTANEOUSLY THEREWITH OR SUBSEQUENTLY. Beta , delta -DIOXOCAPROALDEHYDE IS PREPARED BY REACTING LOWER ALKYL Beta -DIALKOXYPROPIONATES WITH ACETONE UNDER CONDITIONS SUITABLE TO EFFECT THE Claisen condensation reaction.

United States Patent Takasu et al.

[451 May 23, 1972 PROCESS FOR PREPARING 3- HYDROXY-2-METHYL-4-PYRONE[72] Inventors: Ital-u Takasu; Masaru Higuchi; Hiroshl Hotta, all ofOhimachi, Japan [73] Assignee: Daicel Ltd., Osaka, Japan [22] Filed:Oct. 6, 1969 [21] App]. No.: 864,166

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 14.706 6/1968Japan ..260/345.9

OTHER PUBLICATIONS Cavalieri, L. F., Chem. Reviews 1947) p. 529

Letzinger, R. L. et al., low. Am. Chem. Soc., Vol. 83 (1961) pp. 193-I98 Sagredos, A. N. et al., Justus Liebigs Am. Chem. Vol. 697, (l966)pp.Ill-115 Primary ExaminerNorma Milestone Attorney-Woodhams, Blanchard &Flynn ABSTRACT 3-hydroxy-2-methyl-4-pyrone (maltol) is prepared by lreacting B, S-dioxocaproaldehyde dialkyl acetal with lead tetraacetate,(2) either (a) pyrolyzing the product of step l or (b) treating the samewith an acid condensing agent, and (3) hydrolyzing the product of step(2) either simultaneously therewith or subsequently ,8,tS-dioxocaproaldehyde is prepared by reacting lower alkyl,GB-dialkoxypropionates with acetone under conditions suitable to effectthe Claisen condensation reaction.

6 Claims, No Drawings PROCESS FOR PREPARING 3-HYDROXY-2-METHYL-4- PYRONEThe present invention relates to a process for preparing 3-hydroxy-2-methyl-4-pyrone (maltol) which comprises (i) reacting B,S-dioxocaproaldehyde dialkyl acetal represented by the general formula:

(R 0 CHCH COCH COCH (wherein R represents a lower alkyl group havingfrom one to four carbon atoms) with lead tetraacetate, (2) eitherpyrolyzing the resultant oxidatively acetoxylated product or treatingthe same with an acid condensing agent and (3) hydrolyzing the productof step (2) either subsequently or simultaneously with step (2).

The basic route of the reaction in this invention is represented by thefollowing scheme:

Said lower alkyl B, fidialkoxypropionates having the general formula (ROCHCH COOR in which R and R are methyl or ethyl groups, together withtheir preparation methods, are already known. For example, they canreadily be prepared by the reaction between acetic esters and formicesters under the conditions of the Claisen condensation reaction,followed by the preparation of acetals catalyzed by strong acid catalystwith an adequate alkanol from the resulting forrnyl derivatives, or bythe reaction between orthoformic esters and bromoacetic esters by usingzinc.

The Claisen condensation reaction for preparing said compounds (I) fromacetone and lower alkyl B, B-dialkoxypropionates, in which the loweralkyl is preferably methyl or ethyl, is carried out in the presence of abasic condensing agent. As the basic condensing agent, metallic sodium,sodium (wherein R is the same alkyl group referred to above and R and Rrepresent identical or different lower alkyl groups each having one tofour carbon atoms respectively) with acetone under conditions suitablefor efi'ecting the Claisen condensation reaction.

This reaction can be represented by the following general formula:

methoxide and sodium ethoxide are preferred, but other basic condensingagents, such as sodium amide and sodium hydride, can also be employed.As the reaction medium, it is recommended to use an anhydrous loweralkanol or other relatively lower'boiling inert solvent such as diethylether and benzene. The amounts, mole ratios and method of mixing thereactants, the solvent and the basic condensing agent are not criticaland they can be appropriately selected so that the ,3,S-dioxocaproaldehyde dialkyl acetal can be obtained economically. Thereaction temperature is usually selected within the range of 10-80 C.,but this is not critical. After the reaction, the basic components inthe system should be carefully neutralized with an acid neutralizingagent such as formic, acetic, hydrochloric, phosphoric or sulfuric acid,with care being taken to avoid making the system too acidic, thusobtaining B, 6-dioxocaproaldehyde dialkyl acetal.

These compounds (I) are novel as already mentioned and exist as theketo-enol tautomers. They include B, 8-dioxocaproaldehyde dimethylacetal and diethyl acetal, which are chelating agents themselves andwhich can also be used as interrnediates for synthesizing useful organiccompounds such as maltol 3-hydroxy-2-methyl-4-pyrone) according to thepresent invention.

The reaction of this invention for obtaining 3-hydroxy-2-methyl-4-pyrone is carried out by reacting B, d-dioxocaproaldehydedialkyl acetal (I) existing as a mixture of the keto-enol tautomers asshown in the above scheme, with lead tetraacetate in an appropriatesolvent, such as benzene, methanol or acetic acid, and at a temperature,preferably from vC. to the reflux temperature of the solvent used, toeffect oxidative acetoxylation of said acetal. The resultantacetoxylated product substantially consisting of 'y-acetoxy-B,S-dioxocaproaldehyde dialkyl acetal (possibly existing as a mixture oftautomers) (H) is either (a) pyrolyzed at a temperature of more thanabout 150 C. and preferably less than about 300 C. or (b) treated withan acid condensing agent, such as hydrochloric, phosphoric, sulfuric oran organic sulfonic acid, such as p-toluene sulfonic acid, at atemperature of about 0 to 300 C., preferably less than 100 C. Theresultant 3-acetoxy- 2-methyl-4-pyrone (IH) is hydrolyzed to give3-hydroxy-2- methyl-4-pyrone (IV).

The ring closure by means of pyrolysis can be effected simultaneouslywhen the acetoxylated product is distilled under reduced pressure byheating at the above-mentioned temperature. Since the compound (III) canbe rather readily hydrolyzed, the hydrolysis can occur under thepresence of water in the reaction system simultaneously in saidpyrolysis step or in said treatment with an acid condensing agent. Thus,it is possible to make the desired end product (IV) by one step from theacetoxylated product (H).

The amounts, mole ratios and method of mixing the concerned materials isnot critical and can be suitably selected so that the desired endproduct (IV) can be obtained economically.

Lead acetate, which is another product in the oxidative acetoxylationstep, will precipitate in most cases as virtually insoluble crystals inthe system, which is either the reaction mixture or the reaction mixtureafter the solvent has been removed by evaporation. The lead acetate canbe recovered almost quantitatively by only filtering the system. Whenthe recovered lead acetate is oxidized or oxidatively acetoxylated tolead tetraacetate in the conventional manner, such as by using chlorineas an oxidizing agent, it can be reused efi'ectively.

The desired end product (IV) of this invention is commonly known asmaltol. Maltol is useful as a fragrance ingredient, especially as aflavor enhancer for foods. The object of this invention is to provide anovel process for synthesizing maltol which has so far been derived frombiochemical sources alone.

The following Example A and B show preferred procedures of preparing [3,8-dioxocaproaldehyde dialkyl acetals (I) according to this invention.

EXAMPLE A To a mixture of 360 parts by weight of dry diethyl ether(parts(s) by weight will be referred to as part(s)" hereinafter) and 23parts of finely granulated metallic sodium, there was gradually added amixture of acetone (58 parts) and methyl B, B-dimethoxypropionate (148parts) at the reflux temperature of diethyl ether. After finishing theaddition, the

resultant mixture was reacted at 5 to 10 C. for about 2 hours.

The reaction mixture was then neutralized with an aqueous sulfuric acidsolution until it became weakly acidic. The organic layer was separatedand evaporated to remove the solvent. The residue was distilled in vacuoto give [3, S-dioxocaproaldehyde dimethyl acetal (88 parts) showing aboiling temperature of 75-76 C. per 3 mm. Hg. According to IR absorptionspectrum, NMR spectrum, chemical behaviors and results of elementalanalysis as shown below on the crystalline cuprous salt of blue color(melting point: l59-l60 C.) produced by mixing and agitating the productof this reaction with a saturated aqueous solution of cuprous acetate,it was confirmed that the product of this reaction was B.8-dioxacaproaldehyde dimethyl acetal.

Elemental analysis of cuprous salt: Calculated: C 46.88% H 6.39% Found:C 46.99% H 6.40%

It was found that the greater part of this compound existed in theenol-form in a carbon tetrachloride solution at room temperature. Thismaterial was used in the following Examples 1 and 2.

EXAMPLE B To a mixture of dry diethyl ether (I parts) and sodiummethoxide (32 parts), there was added gradually dropwise a mixture ofacetone (29 parts) and ethyl B, fi-diethoxypropionates parts) at thereflux temperature of diethyl ether. After finishing the addition, thereaction mixture was treated in a similar way as mentioned in Example Ato obtain 18,8-dioxocaproaldehyde diethyl acetal (46 parts) showing aboiling temperature of 9799 C. per 4 mm. Hg. According to IR and NMRspectra, chemical behaviors and results of elemental analysis as shownbelow, similar to Example A, it was confirmed that the product of thisreaction was B, S-dioxacaproaldehyde diethyl acetal.

Elemental analysis of cuprous salt: (C l-l,,O Cu Calculated: C 51.55% H7.35% Found: C 50.85% H 7.32%

This material was used in the following Example 3.

The following Examples l to 3 show preferred and practical embodimentsof the process according to the present invention for preparing3-hydroxy-2-methyl-4-pyrone.

EXAMPLE 1 (1) To a mixture of lead tetraacetate (116 parts) and drybenzene (I32 parts), there was added dropwise B, B-dioxocaproaldehydedimethyl acetal (41 parts), and the resultant mixture was reacted at 30to 35 C. for 2 hours. The precipitated lead acetate was filtered ofi.The filtrate was evaporated to remove the solvent and the residue wasdistilled in vacuo to give a distillate consisting mainly of'y-acetoxy-B,8- dioxocaproaldehyde dimethyl acetal. The boiling pointwas 99 to C. per 3 mm. Hg.

(2) The thus obtained distillate (10 parts) was mixed with benzene (26parts) and concentrated sulftu'ic acid (1 part); and the resultantmixture was stirred at 50 to 55 C. for 2 hours. The benzene layer wasseparated and washed with water. The sulfuric acid layer was combinedwith the aqueous washings, neutralized with 15 percent sodium hydroxidesolution and shaken with chloroform. The chloroform layer was evaporatedto remove the solvent and crude crystals of 3- hydroxy-2-methyl-4-pyronewere precipitated. Separately, the benzene layer was evaporated toremove the solvent and a residue containing some crystals and liquid wasobtained. The residue was hydrolyzed with concentrated hydrochloricacid, neutralized and shaken with chloroform. The chloroform layer wasevaporated to remove the solvent and crude crystals of3-hydroxy-2-methyl-4-pyrone were obtained. The total amount of crystalsobtained amounted to about 3 parts. The purified product showed amelting point of 162 to 163 C. No lowering of the melting point wasobserved when the purified product was admixed with an authentic sampleof maltol. The IR and NMR spectra of the purified product were quite inaccordance with those of the authentic maltol sample. The purifiedproduct was subjected to a coloring test with ferric chloride and theresult was positive.

Elemental analysis for C H O Calculated: C 57.14% H 4.80% O 38.06%Found: C 57.32% H 4.89% O 37.79%

EXAMPLE 2 1) To a mixture of B, S-dioxocaproaldehyde dirnethyl acetal(9.2 parts) and glacial acetic acid 105.0 parts), there was added leadtetraacetate (26.0 parts), and the resultant mixture was reacted at 20to 25 C. for 4 hours. The reaction mixture was evaporated to removeacetic acid and the precipitated lead acetate was filtered off. Thefiltrate was distilled in vacuo at 150 to 160 C. (bath temperature) togive a distillate (5.5 parts) consisting mainly of 3-acetoxy-2-methyl-4-pyrone. The boiling point was 1 to 120 C. per 3 mm. Hg.

(2) To the thus obtained distillate (4.6 parts), there was addedconcentrated hydrochloric acid (10.0 parts). The mixture was stirred atroom temperature for 2 hours and then was stirred at 50 to 55 C. for 1hour. The reaction mixture was neutralized with about percent sodiumhydroxide solution and shaken with chloroform. The chloroform layer wasevaporated to give 3-hydroxy-2-methyl-4-pyrone (1.8 parts) as crudecrystals. The sublimed product showed a melting point of 162 to 163 C.and no lowering of the melting point was observed when it was admixedwith an authentic sample of maltol. The IR and NMR spectra of thissubstance were in accordance with those of the authentic maltol sample.The result of the ferric chloride test was positive.

EXAIvfPLE 3 To a mixture of B, B-dioxocaproaldehyde diethyl acetalparts) and benzene (71 parts), there was added lead tetraacetate (50parts) and the mixture was reacted at to C. for 2 hours. Theprecipitated lead acetate was filtered off under suction. The filtratewas concentrated and the remaining liquid was pyrolyzed at 150 to 155 C.per 4 mm. Hg. to give 3-hydroxy-2-methyl-4-pyrone as the sublimedproduct. This substance showed a melting point of 162 to 163 C., and nolowering of the melting point was observed when this substance wasadmixed with an authentic sample of maltol. IR spectrum of this productwas in accordance with that of the authentic maltol sample.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. Process for preparing 3-hydroxy-2-methyl-4-pyrone which comprises (1)reacting ,B, 8-dioxocaproaldehyde dialkyl acetal of the formula:

wherein R is a lower alkyl group having from one to four carbon atoms,with lead tetraacetate, (2) subjecting the resultant oxidativelyacetoxylated product to a ring closing reaction by either (a) pyrolyzingthe resultant oxidatively acetoxylated product, or (b) treating the samewith an acid condensing agent and (3) hydrolyzing the product of step(2) either subsequently or simultaneously to obtain 3-hydroxy-2-methyl-4pyrone.

2. A process as claimed in claim 1, in which said lower alkyl group isselected from the group consisting of ethyl and methyl.

3. A process as claimed in claim 1, in which said oxidativelyacetoxylated product is pyrolyzed at a temperature of more than 150 C.

4. Process for preparing 3-hydroxy-2-methyl-4pyrone which comprises (1)reacting (a) lower alkyl B, B-dialkoxypropionate of the formula:

wherein R and R are identical or different lower alkyl groups eachhaving from one to four carbon atoms respectively, with (b) acetone, inthe presence of (c) a basic condensing agent and (d) an inert solventand then (2) neutralizing the reaction mixture to obtain [3,8-dioxocaproaldehyde dialkyl acetal of the formula:

wherein R has the same meaning as given above, (3) reacting said ,8,fi-dioxocaproaldehyde dialkyl acetal with lead tetraacetate, (4)subjecting the resultant oxidatively acetoxylated product to a ringclosing reaction by either (a) pyrolyzing the resultant oxidativelyacetoxylated product or (b) treating the same with an acid condensingagent and (5) hydrolyzing the product of step (4) either subsequently orsimultaneously to obtain 3-hydroxy-2-methyl-4-pyrone.

5. The process as claimed in claim 4, in which said lower alkyl group isselected from the group consisting of ethyl and methyl.

6. The process as claimed in claim 4, in which said lower alkyl ,8,B-dialkoxypropionate is reacted with acetone at a temperature in therange of from about 10 C. to about C.

2. A process as claimed in claim 1, in which said lower alkyl group isselected from the group consisting of ethyl and methyl.
 3. A process asclaimed in claim 1, in which said oxidatively acetoxylated product ispyrolyzed at a temperature of more than 150* C.
 4. Process for preparing3-hydroxy-2-methyl-4pyrone which comprises (1) reacting (a) lower alkylBeta , Beta -dialkoxypropionate of the formula: (R1O)2CHCH2COOR2 whereinR1 and R2 are identical or different lower alkyl groups each having fromone to four carbon atoms respectively, with (b) acetone, in the presenceof (c) a basic condensing agent and (d) an inert solvent and then (2)neutralizing the reaction mixture to obtain Beta , delta-dioxocaproaldehyde dialkyl acetal of the formula: (R1O)2CHCH2COCH2COCH3wherein R1 has the same meaning as given above, (3) reacting said Beta ,delta -dioxocaproaldehyde dialkyl acetal with lead tetraacetate, (4)subjecting the resultant oxidatively acetoxylated product to a ringclosing reaction by either (a) pyrolyzing the resultant oxidativelyacetoxylated product or (b) treating the same with an acid condensingagent and (5) hydrolyzing the product of step (4) either subsequently orsimultaneously to obtain 3-hydroxy-2-methyl-4-pyrone.
 5. The process asclaimed in claim 4, in which said lower alkyl group is selected from thegroup consisting of ethyl and methyl.
 6. The process as claimed in claim4, in which said lower alkyl Beta , Beta -dialkoxypropionate is reactedwith acetone at a temperature in the range of from about -10* C. toabout 80* C.